Severe asthma, a heterogeneous disease consisting of related clinical phenotypes, generates high levels of morbidity, mortality and health care costs. The complexity and heterogeneity of the disorder have limited clinical advances. However, the NHLBI Severe Asthma Research Program (SARP) has successfully recruited over 1000 asthmatics, including nearly 600 severe asthmatics since 2003. This GRAND OPPORTUNITY will allow us to closely link previous and on-going genome-wide association studies (GWAS) with their molecular profiles and previous and newly identified clinical phenotypes. Unlike any other NHLBI network, bronchoscopies are routinely performed on SARP participants. Epithelial brushings and bronchoalveolar lavage (BAL) cells from these studies will undergo microarray analysis to form the biologic link between the genotype and phenotype. The overall objective of this proposal is to establish the world's most extensive GWAS dataset on adult asthmatics over a range of phenotypes/severity, to develop molecular profiles on a subset of these subjects using cells of relevance to the disease (lung cells) and to then link the genetic and genomic data to greatly speed the identification of targeted pathways of relevance for therapy. The underlying hypothesis is that lung cell gene expression, modulated by the genetic background (GWAS) and the environment (epigenetic profiling), will track with biased and unbiased clinical phenotypes to speed development of novel approaches to asthma therapy. To investigate this hypothesis, analysis of gene expression patterns in cells lung cells of relevance to asthma, will be integrated with whole genome SNP maps of the same patients and their clinical phenotypes. New modules of genes that characterize, define and potentially mechanistically explain the distinct pattern of disease in each phenotype will be identified. In addition, we will have an opportunity to determine whether epigenetic/environmental factors explain the differences between genetic and genomic variation. There are 3 Specific Aims: 1. Establish genetic profiles for adult asthma severity and phenotypes by combining the existing STAMPEED dataset with an additional 3000 GWAS from well characterized adult asthmatics;2. Establish gene expression profiles for adult asthma severity and phenotypes using freshly isolated cells from the target organ (lung) of 200-250 well characterized asthmatics and 50 normal controls;3. Using supervised and unsupervised approaches, generate combined models integrating genetic, genomic, epigenomic and phenomic characteristics to enhance identification of novel molecular therapeutic targets. Public Health Relevance Statement: The aim of this purpose is to study the underlying genomics of asthma, especially severe asthma to determine why some individuals develop more severe and difficult to treat asthma. Our findings will facilitate the development of new therapies especially targeted for severe asthmatics.